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  • 1
    Language: English
    In: The Journal of neuroscience : the official journal of the Society for Neuroscience, 24 January 2018, Vol.38(4), pp.858-877
    Description: Schwann cell differentiation and myelination depends on chromatin remodeling, histone acetylation, and methylation, which all affect Schwann cell proliferation. We previously reported that the deletion of the POZ (POxvirus and Zinc finger) domain of the transcription factor Miz1 (Myc-interacting zinc finger protein; encoded by ) in mouse Schwann cells (Δ) causes a neuropathy at 90 d after birth [postnatal day (P) 90], with a subsequent spontaneous regeneration. Here we show that RNA sequencing from Δ and control animals at P30 revealed a set of upregulated genes with a strong correlation to cell-cycle regulation. Consistently, a subset of Schwann cells did not exit the cell cycle as observed in control animals and the growth fraction increased over time. From the RNAseq gene list, two direct Miz1 target genes were identified, one of which encodes the histone H3K36 demethylase Kdm8. We show that the expression of is repressed by Miz1 and that its release in Δ cells induces a decrease of H3K36, especially in deregulated cell-cycle-related genes. The linkage between elevated expression, hypomethylation of H3K36 at cell-cycle-relevant genes, and the subsequent re-entering of adult Schwann cells into the cell cycle suggests that the release of repression in the absence of a functional Miz1 is a central issue in the development of the Δ phenotype. The deletion of the Miz1 (Myc-interacting zinc finger protein 1) POZ (POxvirus and Zinc finger) domain in Schwann cells causes a neuropathy. Here we report sustained Schwann cell proliferation caused by an increased expression of the direct Miz1 target gene , encoding a H3K36me2 demethylase. Hence, the demethylation of H3K36 is linked to the pathogenesis of a neuropathy.
    Keywords: Kdm8 ; Miz1 ; Schwann Cell ; Histone Demethylation ; Peripheral Neuropathy ; Proliferation ; Demyelinating Diseases -- Metabolism ; Jumonji Domain-Containing Histone Demethylases -- Metabolism ; Nuclear Proteins -- Metabolism ; Peripheral Nervous System Diseases -- Metabolism ; Protein Inhibitors of Activated Stat -- Metabolism ; Schwann Cells -- Metabolism
    ISSN: 02706474
    E-ISSN: 1529-2401
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  • 2
    In: PLoS ONE, 2015, Vol.10(4)
    Description: RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS , as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog ( MEIS1 ) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies.
    Keywords: Research Article
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Nucleic acids research, 21 August 2018, Vol.46(14), pp.7097-7107
    Description: The two paralogous zinc finger factors CTCF and CTCFL differ in expression such that CTCF is ubiquitously expressed, whereas CTCFL is found during spermatogenesis and in some cancer types in addition to other cell types. Both factors share the highly conserved DNA binding domain and are bound to DNA sequences with an identical consensus. In contrast, both factors differ substantially in the number of bound sites in the genome. Here, we addressed the molecular features for this binding specificity. In contrast to CTCF we found CTCFL highly enriched at 'open' chromatin marked by H3K27 acetylation, H3K4 di- and trimethylation, H3K79 dimethylation and H3K9 acetylation plus the histone variant H2A.Z. CTCFL is enriched at transcriptional start sites and regions bound by transcription factors. Consequently, genes deregulated by CTCFL are highly cell specific. In addition to a chromatin-driven choice of binding sites, we determined nucleotide positions critical for DNA binding by CTCFL, but not by CTCF.
    Keywords: Chemistry ; Anatomy & Physiology;
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 September 2017, Vol.114(38), pp.E8035-E8044
    Description: Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded by ) in skin physiology, we crossed mice harboring floxed with mice expressing K14-Cre-ER to generate mice in which tamoxifen induces the deletion of exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14-Cre-ER CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte-stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.
    Keywords: Kit Ligand ; Casein Kinase 1α ; Melanocyte ; P53 ; Sunburn ; Skin Pigmentation ; Casein Kinase I -- Metabolism ; Keratinocytes -- Metabolism ; Sunburn -- Metabolism ; Tumor Suppressor Protein P53 -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 December 2016, Vol.113(52), pp.E8433-E8442
    Description: Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.
    Keywords: Entpd5 ; N-Glycosylation ; Metastasis ; P53 ; Tumor Suppressor ; Neoplasm Metastasis ; Endoplasmic Reticulum -- Metabolism ; Oncogene Proteins -- Metabolism ; Pyrophosphatases -- Metabolism ; Tumor Suppressor Protein P53 -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: Journal of Bioinformatics and Computational Biology, February 2014, Vol.12(1)
    Description: Predicting the sub-cellular localization of proteins is an important task in bioinformatics, for which many standard prediction tools are available. While these tools are powerful in general and capable of predicting protein localization for the most common compartments, their performance strongly depends on the organism of interest. More importantly, there are special compartments, such as the apicoplast of apicomplexan parasites, for which these tools cannot provide a prediction at all. In the absence of a highly conserved targeting signal, even motif searches may not be able to provide a lead for the accurate prediction of protein localization for a compartment of interest. In order to approach difficult cases of that kind, we propose an alternative method that complements existing approaches by using a more targeted protein sequence model. Moreover, our method makes use of (weighted) measures for time series comparison. To demonstrate its performance, we use this method for predicting localization in special compartments of three different species, for which existing methods yield only sub-optimal results. As shown experimentally, our method is indeed capable of producing reliable predictions of sub-cellular localization for difficult cases, i.e. if training data is scarce and a potential protein targeting signal may not be well conserved.
    Keywords: Protein Sub-Cellular Localization ; Time Series Metrics ; Localization Prediction ; Biology
    ISSN: 0219-7200
    E-ISSN: 1757-6334
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  • 7
    Language: English
    In: Nucleic acids research, 20 April 2016, Vol.44(7), pp.3204-18
    Description: TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathway in vivo Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.
    Keywords: DNA Repair ; Antineoplastic Agents -- Therapeutic Use ; Carcinoma, Squamous Cell -- Genetics ; Cisplatin -- Therapeutic Use ; Transcription Factors -- Metabolism ; Tumor Suppressor Proteins -- Metabolism
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 8
    Language: English
    In: IEEE/ACM Transactions on Computational Biology and Bioinformatics (TCBB), 01 September 2011, Vol.8(5), pp.1330-1343
    Description: Comparative analysis is a topic of utmost importance in structural bioinformatics. Recently, a structural counterpart to sequence alignment, called multiple graph alignment, was introduced as a tool for the comparison of protein structures in general and protein binding sites in particular. Using approximate graph matching techniques, this method enables the identification of approximately conserved patterns in functionally related structures. In this paper, we introduce a new method for computing graph alignments motivated by two problems of the original approach, a conceptual and a computational one. First, the existing approach is of limited usefulness for structures that only share common substructures. Second, the goal to find a globally optimal alignment leads to an optimization problem that is computationally intractable. To overcome these disadvantages, we propose a semiglobal approach to graph alignment in analogy to semiglobal sequence alignment that combines the advantages of local and global graph matching.
    Keywords: Approximate Graph Matching, Protein Binding Sites, Structure Comparison, Graph Alignment, Structural Bioinformatics ; Biology
    ISSN: 1545-5963
    E-ISSN: 1557-9964
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  • 9
    Language: English
    In: Molecular Informatics, July 2012, Vol.31(6‐7), pp.443-452
    Description: A key task in structural biology is to define a meaningful similarity measure for the comparison of protein structures. Recently, the use of graphs as modeling tools for molecular data has gained increasing importance. In this context, kernel functions have attracted a lot of attention, especially since they allow for the application of a rich repertoire of methods from the field of kernel‐based machine learning. However, most of the existing graph kernels have been designed for unlabeled and/or unweighted graphs, although proteins are often more naturally and more exactly represented in terms of node‐labeled and edge‐weighted graphs. Here we analyze kernel‐based protein comparison methods and propose extensions to existing graph kernels to exploit node‐labeled and edge‐weighted graphs. Moreover, we propose an instance of the substructure fingerprint kernel suitable for the analysis of protein binding sites. By using fingerprints, we solve the problem of discontinuity on bin‐boundaries arising in the case of labeled graphs.
    Keywords: Proteins ; Drug Design
    ISSN: 1868-1743
    E-ISSN: 1868-1751
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  • 10
    Language: English
    In: Journal of Cheminformatics, 3/2013, Vol.5(S1)
    Description: The problem of estimating the similarity between molecular structures is often tackled by means of graph-based approaches, using graphs for structure representation and measures based on the maximum common subgraph as similarity metrics. In the case of protein binding sites as molecular structures, however, where the graphs can be very large, the computation of these measures may easily become infeasible or at least unacceptably slow.
    Keywords: Chemistry;
    ISSN: Journal of Cheminformatics
    E-ISSN: 1758-2946
    Source: CrossRef
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